Coating layers for medical devices and methods of making the same

ABSTRACT

Methods are disclosed for controlling the morphology and the release-rate of active agent from coating layers for medical devices comprising a polymer matrix and one or more active agents. The methods comprise fixing the morphology or phase distribution of the active agent prior to removing solvent from the coating composition. The coating layers can be used for controlled the delivery of an active agent or a combination of active agents.

TECHNICAL FIELD

The present invention relates generally to the field of medical devices,particularly implantable medical devices, and to methods for coatingsuch devices with layers comprising a polymer matrix and one or moreactive agents. More particularly, this invention pertains to methods forcontrolling the morphology of coating layers and the phase distributionof components within the coating layer. This invention further pertainsto methods for designing and controlling active agent release-rates fromcoating layers for medical devices.

BACKGROUND

In the area of medical devices, biomaterials research continues tosearch for new compositions and methods to improve and control theproperties of the medical devices. This is particularly true for medicalarticles that are implantable within a subject, where predictable andcontrollable performance is essential to the successful treatment of asubject.

An example of an implantable medical device is a stent. Stents can actas a mechanical means to physically hold open and, if desired, expand apassageway within a subject. Typically, a stent is compressed, insertedinto a small vessel through a catheter, and then expanded to a largerdiameter once placed in a proper location. Stents play an important rolein a variety of medical procedures such as, for example, percutaneoustransluminal coronary angioplasty (PTCA), a procedure used to treatheart disease by opening a coronary artery blocked by an occlusion.Stents are generally implanted in such procedures to reduce occlusionformation, inhibit thrombosis and restenosis, and maintain patencywithin vascular lumens. Examples of patents disclosing stents includeU.S. Pat. Nos. 4,733,665; 4,800,882; and 4,886,062.

Stents are also being developed to locally deliver active agents, e.g.drugs or other medically beneficial materials. Local delivery is oftenpreferred over systemic delivery, particularly where high systemic dosesare necessary to affect a particular site. For example, agent-coatedstents have demonstrated dramatic reductions in stent restenosis ratesby inhibiting tissue growth associated with restenosis.

Proposed local delivery methods from medical devices include coating thedevice surface with a layer comprising a polymeric matrix and attachingan active agent to the polymer backbone or dispersing, impregnating ortrapping the active agent in the polymeric matrix. For example, onemethod of applying an active agent to a stent involves blending theagent with a polymer dissolved in a solvent, applying the composition tothe surface of the stent, and removing the solvent to leave a polymermatrix in which an active agent is impregnated, dispersed or trapped.During evaporation of the solvent, phase separation candisadvantageously occur, often resulting in hard-to-control processconditions and a drug coating morphology that is difficult to predictand control. This makes delivery of the agent unpredictable.

Further, manufacturing inconsistencies among different stents can arisewith the above coating method. For example, release-rate variability hasbeen observed among supposedly identical stents made by the sameprocess. Apparently, when some polymer coatings comprising active agentsdry on the surface of a medical device different morphologies develop indifferent coatings, even if the coating process parameters areconsistent. These differences in coating morphology may cause activeagent release-rates from different stents to vary significantly. As aconsequence of the inconsistent release-rate profiles among stents therecan be clinical complications. Thus, there is a need for methods thatcan control the variability of active agent release-rates among medicaldevices and provide manufacturing consistency.

Morphological changes that affect release-rates of active agents havebeen observed to be dependent on the active agent phase in the polymermatrix. When a coating composition is applied to the surface of amedical device the active agent is initially evenly dispersed in thecoating composition. However, during processing the agent may migrate orphase separate to form different phase regions within the coating layer.These regions are often connected with each other and are referred to asthe percolation phase. The mass transport properties of active agentsare distinct through the percolation phase. Mass transport through thepercolation phase is driven by the solubility of active agent in therelease medium, the diffusivity of the active agent in the releasemedium, and the morphological feature of the percolated phase such as,for example, tortuosity and area fraction. The release-rate of theactive agent is often greatly increased from these regions or phases.The formation of percolated phases is particularly pronounced at highactive agent concentrations, for example above about 35% by volumefraction of active agent to polymer in the coating layer.

Those skilled in the art will therefore appreciate that local deliverywould benefit not only from improved release-rate profiles that arecontrolled and predictable, but also from manufacturing improvementsthat would provide consistency. Thus, methods for making coated medicaldevices with more reliable performance are highly desirable andessential to providing effective treatment of patients. In addition,control over the release-rate can assist in designing and maintainingthe physical and mechanical properties of medical devices and coatings,as well.

SUMMARY

According to one aspect of the present invention, methods are providedfor controlling the morphology of coating layers for medical devicescomprising a polymer matrix and one or more active agents. A furtheraspect of the present invention provides coated medical devices with acontrolled release-rate of one or more active agents by selecting thephase distribution of the active agent phases in the layer.

In some embodiments, the coating layer morphology is controlled byfixing the active agent morphology in a wet coating layer comprising oneor more polymers, one or more active agents and one or more solvents.Methods to fix the active agent morphology or phase distributioninclude, but are not limited to, exposing to cold gas, dipping in coldliquid, exposing to shock freezing, exposing to flash vaporization,exposing to non-solvent exchange, and combinations thereof. In analternative method, the active agent morphology is fixed bycross-linking the polymer matrix. After the active agent morphology isfixed, solvent is removed from the wet coating layer by a method suchas, for example, evaporation, freeze-drying, non-solvent exchange,critical point drying, and combinations thereof. In one embodiment,solvent is removed by a combination of non-solvent exchange with CO₂ andcritical point drying. According to a further embodiment of the presentinvention, a portion of the solvent is removed from the wet coatinglayer prior to fixing the active agent morphology. This allowsmodulation of the active agent phase distribution in the coating layer.Further, the embodiments of the present invention may includepost-formation processing steps, such as annealing, applying a top coatand/or finishing layer, or sterilization.

According to another aspect of the present invention, selecting thephase distribution of the active agent in the polymer matrix controlsthe release-rate profile of active agent from a medical device coatinglayer. In one embodiment, the active agent phase, or phases, is fixedduring coating layer formation controlling the phase distribution of theactive agent. In one embodiment, the active agent phase distribution inthe coating layer comprises one or more phases selected from dissolved,dispersed, and percolated phases. In one embodiment, the release-rateprofile of active agent is determined by the ratio of the phases of theactive agent in the coating layer.

The coating layers of the present invention may be applied to a varietyof medical devices. In one embodiment, the medical device is a stent.Active agents useful in these coating layers can vary widely. In oneembodiment the active agent is selected from the group consisting ofantiproliferative, antineoplastic, anti-inflammatory, steroidalanti-inflammatory, non-steroidal anti-inflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,antiallergic, antioxidant, cytostatic agents, and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows a ternary phase diagram for polymer, active agent andsolvent coating compositions of the present invention.

DETAILED DESCRIPTION

As discussed in further detail below, the present invention generallypertains to coating layers for medical devices, particularly implantablemedical devices, comprising a polymer matrix and one or more activeagents. The present invention also provides methods for forming coatinglayers for medical devices comprising a polymer matrix and one or moreactive agents, where the morphology of the coating layer and the phasedistribution of the active agent within the layer are controlled byprocess parameters. Further, the present invention pertains to methodsfor controlling the morphology of coating layers, and the release-rateof active agent from the layer, by fixing the active agent phase duringformation of the coating layer.

By controlling the morphology of the coating layer during formation, andparticularly the active agent phase distribution within it, therelease-rates of the active agent(s) from the coating layer can be moreeffectively controlled and manufacturing inconsistencies reduced oreliminated. Thus, improved therapeutic, prophylactic or other biologicaleffects may be realized in the treatment of a subject. The use ofprocess parameters in the methods of the present invention instead ofadditional excipients to control active agent release-rates providesadvantages in the design of controlled release systems. Further, thecontrol of active agent release-rates has positive implications for themechanical integrity of the polymeric matrix, as well as a relationshipto a subject's absorption rate of absorbable polymers.

There are many considerations in designing, controlling or predictingthe active agent release-rates from a coating layer comprising a polymermatrix and one or more active agents. These include, but are not limitedto, the morphology of the coating layer and components in the layer; thesize and shape of the active agent; the active agent phase and thedistribution of phases in the layer; the selection and the concentrationof active agent or agents; the presence of polymorphism of the agents;the polymer or polymers forming the polymer matrix; the presence offunctional groups on the polymers; the hydrophilicity or hydrophobicityof the polymer matrix; the presence of other additives in thecomposition, for example, fillers, metals, plasticizing agents,cross-linking agents; and the degree, if any, of bonding between thepolymer matrix and the active agent(s).

The morphology of the coating layer is particularly important indetermining the performance characteristics of coating layers, becausethe distribution of active agent and the phases of active agent withinthe polymer matrix directly relate to the active agent release-rateprofile. In particular, phase separation that may occur between thesolvent and the active agents and polymers of the matrix duringformation of the coating layer is key to determining the coating layermorphology and the active agent release-rate profile. Thus, one of thegoals of the present invention is to provide methods for controlling themorphology of coating layers comprising a polymer matrix and one or moreactive agents by controlling phase separations that can occur whensolvent is removed from the coating composition. Yet another goal iscontrolling the polymer-matrix-active-agent morphology within thecoating layers to provide layers with predictable active agentrelease-rates. The methods of the present invention use processparameters to control coating layer morphology and phase distribution ofthe active agent in the polymer matrix. The methods of the presentinvention can either decrease or increase active agent release-rates. Afurther aspect of the present invention provides methods for enhancedprocess control and coating reproducibility for medical articles anddevices comprising a polymer matrix and one or more active agents.

The term “morphology” as used herein refers to the way in which apolymer matrix, optionally active agents, and optionally othercomponents, lie in a coating layer after solvent removal. The morphologycan be defined in terms of properties such as the shape, structure, formor phase of components in the coating layer. The term “configuration” isalso used herein to refer to the morphology of the coating layer. Inparticular, morphology is used herein to describe the phase or phases ofactive agent and/or the arrangement of the active agent phase(s) in thepolymer matrix and the distribution of those phases within the coatinglayer.

The morphology of the coating layer can be defined, for example, by thepresence and characteristics of phase separation between componentswithin the coating, where the phase separation can exist betweenpolymers of the matrix, an agent and a polymer, between agents, orbetween other components in the polymeric matrix. In one embodiment, thecoating layer morphology is defined by the phase distribution of the oneor more active agent phases within the polymer matrix. In otherembodiments, the morphology can be defined, for example, by thecharacteristics of the zone of phase separation, where the zone of phaseseparation can be thin, thick, continuous, non-continuous, hydrophobic,hydrophilic, porous, interconnected, dispersed, and the like. In someembodiments, the morphology can be defined, for example, by otherphysical characteristics of the polymeric matrix including, but notlimited to, the presence of pores, crystalline or semi-crystallineregions, amorphous regions, metals, ceramics, the existence ofpolymorphism in agents, and the like. Any coating property that would beconsidered a morphological characteristic to one of skill in the art iswithin the scope of the present invention. The morphology can becharacterized by any method or measurement known in the art tocharacterize layers comprising polymers.

The “phase” of a component of the coating layer can be defined, forexample, by the crystallinity, semi-crystallinity, liquid crystallinity,orientation, or polymorphic state of the component. The “phase” of acomponent can also be defined by a distinct arrangement and/ordispersion of a component, or a fraction of a component, in the coatinglayer. In particular, the term “active agent phase” is used herein torefer to a physically distinct arrangement and/or distribution of someor all of the active agent species within the polymer matrix of thecoating layer. The term “phase distribution” as used herein refers tothe one more phases of a component present in the coating layer. Inparticular, phase distribution is used to refer to the distribution ofone or more active agent phases in a coating layer. In one embodiment,the phase distribution of the active agent in the coating layercomprises one or more active agent phases.

The formation of an active agent phase depends on the thermodynamics andkinetics of processing. An example of a ternary phase diagram for apolymer-active-agent-solvent system is shown in FIG. 1. Kinetics ofprocessing can be further subdivided into internal kinetic timeconstants and external time constants. Internal time constants include,for example, crystallization and migration rate of active agents.External time constants include, for example, the rate of solventremoval from the wet coating layer.

The methods and embodiments of the present invention are most usefulwhere the active agent is blended with, dissolved in, impregnated,trapped or distributed in the polymer matrix. This means the activeagent exists molecularly, at a molecular size, surrounded by polymermolecules of the polymer matrix. In some of these types of embodiments,the active agent is not covalently attached to the polymer matrix. Therelease, and hence the release-rate, of the active agent from thecoating layer depends on the ability of the active agent to diffusethrough the polymer matrix. This diffusion depends on the active agentphase in the layer and the transport properties of the polymeric matrix.It is one of the goals of the present invention to modulate or controlthe active agent phase and hence control the release-rate of the activeagent from the coating layer.

In some embodiments, the active agent exists in the coating layer in adissolved, dispersed or percolated phase. Typically, a coating layerwill comprise some fraction of all three active agent phases. Withoutbeing bound by any particular theory, it is believed that the ratio ofthe co-existing phases is a function of the volume fraction of activeagent to polymer in the coating layer, as well as the active agent'sphysicochemical properties, such as its solubility in the polymermatrix. Thus, at low active-agent-to-polymer ratios, for example belowabout 10% by volume fraction active agent to polymer, the active agentphase will predominantly be a dissolved phase. As the percentage ofactive agent increases, the fraction of the other phases mixed with thedissolved phase increases.

In one embodiment, the active agent of the coating layer is in adissolved phase. In one embodiment, the active agent of the coatinglayer is in a dispersed phase. In one embodiment, the active agent ofthe coating layer is in a percolated phase. In one embodiment, theactive agent of the coating layer comprises a mixed phase, wherein thephase distribution comprises two or more phases selected from the groupconsisting of dissolved, dispersed, or percolated phases. In oneembodiment, the active agent phase distribution comprises dissolvedphase, dispersed phase and percolated phase. In some embodiments, oneactive agent phase can primarily be present in the coating layer,whereby the particular phase is present in an amount greater than anyother phase in the coating layer. In one embodiment, the active agentphase distribution comprises primarily dissolved phase. In oneembodiment, the active agent phase distribution comprises primarilydispersed phase. In one embodiment, the active agent phase distributioncomprises primarily dissolved and dispersed phases. The percentage of anactive agent phase present in a coating layer can be controlled by themethods described herein.

As used herein, dissolved phase refers to an active agent phase in whichthe active agent is dissolved in the solid polymer matrix as in a solidsolution. In other words, the active agent species are not closelyassociated with other active agent species within the coating layer andare surrounded by polymer molecules of the polymer matrix. Dissolvedphases occur particularly at low active agent concentrations, where theconcentration is measured as a volume fraction of the active agent topolymer in the coating layer. For example at concentrations below about10% by volume fraction of active agent to polymer in the coating layer,and also in coating layers where no phase separation occurs between thesolvent, polymer matrix and active agent. Additionally, the presence ofdissolved phase depends on the active agent solubility in polymer matrixpolymers. At higher volume fractions, the dissolved phase usuallyco-exists with other active agent phases. In one embodiment, the amountof dissolved phase in the coating layer is equal to or greater than theamount of either dispersed or percolated phase. The phase ratiosdepending on, for example, the active agent concentration, the degree ofphase separation, and the active agent solubility in polymer matrixpolymers.

At active agent concentrations of about 10% or greater by volumefraction of active agent to polymer the active agent may coalesce toform dispersed phase. As used herein, a dispersed phase refers to aphase where a number of active agent species coalesce to form activeagent particles or clusters throughout the coating layer that aresurrounded by polymer matrix polymer molecules. Dispersed phases canalso form at lower concentrations depending on the solubility of activeagent in the polymer matrix.

As used herein, percolated phase refers to an active agent phase whereactive agent molecules significantly migrate and/or phase separate inthe polymer matrix during formation of the coating layer formingconnected pathways of active agent throughout the polymer. When theactive agent is present in the percolated phase, there is less controlover the active agent release-rate than when the active agent is in thedissolved or dispersed phase, because the random connected pathways ofactive agent provide a means for the active agent to diffuse out of andbe released from the coating layer. Thus, the presence of percolatedactive agent phase has a significant affect on the release-rate of theactive agent from the coating layer The presence of percolated phaseincreases the active agent release-rate. The mass transport propertiesof active agents are distinct through the percolation phase. The masstransport through the percolation phase is driven by the solubility ofactive agent in the release medium, the diffusivity of the active agentin the release medium, and the morphological feature of the percolatedphase such as, for example, tortuosity and area fraction. The percolatedphase is most often observed at active agent concentrations of about 35%or greater by volume fraction of active agent to polymer in the coatinglayer, but may also form at lower concentrations depending on thesolubility of the active agent in the polymer matrix. The active agentconcentration at which percolated phase becomes the predominant phase isreferred to herein as the “percolation threshold.” The active agentconcentration at which the percolation threshold is observed depends onfactors including, for example, the choice of active agent, polymermatrix and solvent, as well as the those described below. In someembodiments of the present invention, the concentration of active is atthe percolation threshold and the active agent is primarily in a phaseother than the percolated phase.

Percolate phase formation kinetics depend on a number of factorsincluding the active agent concentration, the solvent phase, the solventused, the mobility of active agent, the temperature at which solvent isremoved, the method of removing solvent and other processes conditions,such as the environment in which drying occurs. By using the methodsdescribed herein to fix the active agent phase in a desired phase orphase distribution before solvent removal, the degree of phaseseparation and dispersion of active agent within the polymer matrix canbe controlled. Thus, a phase distribution profile and morphology of thecoating layer can be created that provides a controllable release-rateprofile for the active agent. Further, by fixing the active agent in adissolved or dispersed phase at higher active agent concentrations morecontrol on the release-rate is obtained because formation of percolatedphase is prevented or greatly reduced. In one embodiment, percolatedphase formation kinetics at high active agent concentrations arecontrolled by fixing the active agent phase distribution after coating adevice with a coating composition. Another aspect of the presentinvention is to control or prevent concentration gradients of activeagents from forming in the coating layer, by fixing the active agentphase distribution before removing solvent from the wet coating layer.

The coating layers of the present invention comprise a polymer matrix,including one or more polymers and one or more active agents.Optionally, the coating layer may further comprise one or more additivesor other components. Typically, coating layers are formed by blendingone or more active agents together with one or more polymers dissolvedin a solvent to form a coating composition, applying the coatingcomposition to a medical device surface, and removing the solvent toleave on the device active agent(s) dispersed in a polymer matrix. Themorphology of the coating layer comprising a polymer matrix and one ormore agents, and the phase distribution of the active agent within thatlayer, and hence the agent release-rate from the layer, can beprofoundly affected by the manner in which the coating layer is formedand the solvent is removed from the coating composition to form acoating layer. When solvent is removed during drying, active agentdispersion and configuration within the coating layer can change due tophase separation between the solvent, and the polymer and active agentphase. This results in a coating layer morphology and distribution ofactive agent that is difficult to predict and control. The presentinvention provides methods to fix the configuration of the active agentphase and/or phase distribution prior to removing the solvent from thecoating composition. In some embodiments, the methods use processparameters to control the release-rate.

One embodiment of the present invention provides methods to control thecoating layer morphology by fixing the active agent morphology before orduring solvent removal from the coating composition. In some of theseembodiments, solvent removal forms a dried coating layer. The coatingcomposition after being deposited on a device surface is referred to asa “wet coating layer.” As used herein the term “wet coating layer”refers to a coating composition comprising solvent that has been appliedto the surface of a device. A coating layer is referred to as wet untilessentially all the solvent is removed from the coating layer. In theembodiments of the present invention solvent in a wet coating layer maynot necessarily be in a liquid state. In one embodiment, the activeagent morphology is fixed prior to solvent removal from the coatingcomposition. Fixing the desired morphology and distribution of theactive agent within the polymer matrix greatly reduces or prevents phaseseparation or the formation of undesired active agent phases such as,for example, dispersed or percolated phases. After the desired activeagent morphology is fixed, solvent is removed to form a coating layerwithout affecting the fixed active agent morphology. In otherembodiments, a fraction of solvent is removed before the morphology ofthe polymer matrix and active agent is fixed. This removal helpsmodulate the degree of phase separation and the distribution of activeagent phases in the layer, and hence helps control the active agentrelease-rate. The present invention is especially useful forcompositions with a high active-agent-to-polymer ratio, where phaseseparation or percolated phase formation are more likely. The methods ofthe present invention may further control or modulate the development ofactive agent concentration gradients within the polymer matrix.

Generally, invention coating layers provide for less variablerelease-rates of active agents from the coatings layers. While not beingbound by any theory, apparently the fixing process renders the coatinglayer's thermo-mechanical and morphological properties less sensitive tosubsequent processing. Apparently, controlling coating layer morphology,and hence active agent release-rates, can control or eliminatemanufacturing inconsistencies.

Methods of Forming Coating Layers

The present invention provides methods for forming a coating layer for amedical device with a controlled active agent morphology. In oneinvention embodiment, fixing the active agent phase distribution whileforming the coating layer controls the active agent release-rate.

In one embodiment of the present invention, a method for controllingcoating layer morphology for a medical device comprising a polymermatrix and one or more active agents, comprises:

-   -   (a) preparing a coating composition comprising one or more        polymers, one or more active agents, and one or more solvents;    -   (b) applying the coating composition onto a medical device to        form a wet coating layer;    -   (c) fixing the morphology of the one or more active agents; and    -   (d) removing the one or more solvents from the wet coating layer        to form a coating layer.

In some embodiments of the present invention, forming a medical devicecoating layer with a controlled active agent morphology comprises:

-   -   (i) preparing a coating composition comprising one or more        polymers, one or more active agents, and one or more solvents;    -   (ii) applying the coating composition onto a medical device to        form a wet coating layer;    -   (iii) removing a fraction of the one or more solvents from the        wet coating layer;    -   (iv) fixing the active agent morphology; and    -   (v) removing the remaining solvent(s) to form a coating layer.

As used herein the terms “fix,” “fixed,” “fixes” or “fixing” are usedinterchangeably to refer to where a component of the coating layer isrestricted or prevented from changing its morphology or phasedistribution so that the morphology or phase distribution becomesinsensitive to subsequent process steps. This definition appliesprincipally to the active agent component and not to the polymer matrixof the coating layer. Although the morphology of the polymer matrix canalso be fixed, it is more likely to change during post-processing steps,for example annealing. When fixed the morphology, configuration or phaseof a component substantially remains in that phase, and does notsignificantly change to other phases when the coating layer is subjectedto further process steps. For example, fixing an active agent in thedissolved phase prevents, restricts, or greatly reduces movement ordiffusion of the active agent to form other phases, thus preserving anearlier-in-time active agent phase distribution. When fixed, themolecular arrangement in the coating layer will usually not be inthermodynamic equilibrium.

Embodiments of the present invention may further comprise after step(d), or step (v) one or more optional post-formation process steps. Forexample, post-formation process steps include, but are not limited to,annealing the coating layer, applying a topcoat or barrier layer to thesurface of the polymer-matrix-active-agent coating layer, applying anoptional finishing coat layer, and sterilization. Other post-processsteps or combinations of post-process steps may also be used in thepractice of the invention. In one embodiment, the methods comprisesubjecting the coating layer formed in step (d) or (v) to one or morepost-formation process steps.

Various methods can be employed in embodiments of the present inventionto fix the morphology or configuration of the one or more active agentsof the coating layer. Suitable methods to fix the active agentmorphology include, but are not limited to, rapidly cooling the wetcoating layer by exposing it to a cold gas; freezing the wet coatinglayer by dipping it into a cold liquid, for example, liquid nitrogen;exposing to shock freezing by applying the coating composition to acooled device surface; exposing to flash vaporization by applying thecoating composition to a hot device surface; and exposing to non-solventexchange by exchanging the solvent for a non-solvent for the activeagent. Other methods to fix the active agent configuration include, butare not limited to, cross-linking the polymer matrix.

In one embodiment of the present invention, rapid cooling is used to fixthe active agent morphology. In some embodiments, the coatingcomposition is applied onto the medical device and then rapidly cooled,for example by exposing the wet coating layer to cold liquid, cold gas,or other low temperature environment. For example, the coatingcomposition can be applied to a stent, and the stent then can be dippedin liquid nitrogen or exposed to cold gas to fix the configuration.Other cold liquids may also be used to rapidly cool the coating layer.Typically, the coating composition is cooled to a temperature of 10° C.or less, alternatively 0° C. or less, −10° C. or less, −20° C. or less,−50° C. or less, −100° C. or less, −150° C. or less, and −180° C. orless. Any solvent remaining in the coating layer after the desiredconfiguration is fixed can subsequently be removed, for example, bysublimation (freeze-drying) or other suitable method.

Without being bound by any particular theory, fixing the active agentmorphology in the coating layer prior to removing the solvent and dryingthe layer apparently locks the active agent into a desired configurationrendering the thermo-mechanical and morphological properties of theactive agent and coating layer insensitive to subsequent processparameters, such as, for example, removing solvent, drying the coating,annealing and sterilizing, as well as improving the device shelf-life.This significantly avoids or prevents forming dispersed or percolatedphases due to phase separation and helps control the active agentrelease-rate.

In another embodiment of the present invention, the active agentconfiguration is fixed by exposing to shock freezing at the time thecoating composition is deposited onto the medical device surface.Depositing the coating composition onto a surface of a cooled medicaldevice can accomplish this. Typically, the device is cooled to atemperature of 10° C. or less, alternatively 0° C. or less, −10° C. orless, −20° C. or less, −40° C. or less, −70° C. or less, −100° C. orless, −150° C. or less, and −200° C. or less. Subsequently, sublimation(freeze drying) or other suitable method removes any remaining solvent.

In one embodiment of the present invention, flash vaporization of thesolvent while depositing the coating composition fixes the active agentconfiguration. Without being bound by any theory, rapidly vaporizing oratomizing the solvent phase during deposition of the coating compositionapparently locks the active agent morphology, and controls therelease-rate profile of the active agent by, for example, preventingdispersed or percolated phase formation. For example, spraying thecoating onto a hot medical device may cause this to occur. In oneembodiment of the present invention, depositing the coating compositiononto a hot medical device is used to fix the polymer-matrix-active-agentconfiguration. Applying the coating composition onto a hot surfaceimmediately atomizes or flash vaporizes the volatile solvent, therebyfixing or locking the active agent into the desired configuration. Whenflash vaporization is chosen to fix the active agent configuration, thesolvent should be selected to readily evaporate or atomize. Typically,the surface is heated to a temperature of 30° C. or more, alternatively45° C. or more, 60° C. or more, 75° C. or more, 100° C. or more, 150° C.or more, 200° C. or more, 300° C. or more, and 400° C. or more.Depositing the coating composition onto a hot surface may also fix theactive agent morphology by initiating polymer matrix cross-linking forthose compositions comprising cross-linking agents, groups, orinitiators. Residual solvent remaining in the coating layer may beremoved by one of the methods described herein.

In yet other embodiments, the coating layer configuration is fixed afterapplying the coating composition to a device in a solvent-saturatedatmosphere. Depositing the coating layer in a saturated solventatmosphere minimizes solvent loss due to evaporation from the appliedcoating composition. These conditions minimize morphology changes, suchas active agent precipitation in the coating layer due to solvent loss,preserving the as-coated polymer matrix and active agent morphologies.In some embodiments, this is done to minimize solvent losses whenapplying the coating composition by spray atomization, where between80-90% of the solvent is normally lost.

In yet another embodiment of the present invention, exposing the coatinglayer to a non-solvent for the active agent controls thepolymer-matrix-active-agent configuration. For example, this may beaccomplished by exposing the polymer-matrix-active-agent coating layerto a non-solvent for the active agent, whereby the non-solvent isexchanged for the solvent. By controlling the non-solvent exchangekinetics a coating layer morphology can to be selected with a desiredactive agent phase distribution. In some embodiments, the non-solventfor the active agent should be miscible with the coating compositionsolvent. Examples of suitable non-solvents for the active agentsinclude, but are not limited to, supercritical CO₂, isopropyl alcohol,acetone, heptane and hexane, and blends thereof. Other examples ofsuitable solvents include, but are not limited to, fluorocarbons andchlorofluorocarbons such as, for example, Freon™ and HCFC 141b(dichlorofluoroethane), and blends of fluorocarbons and alcohol such as,for example, dichlorofluoroethane blended with ethanol. Non-solventexchange may be carried out by method such as, for example, liquid,spray or vapor mist contact. The active agent non-solvent issubsequently removed to form a coating layer by one of the methodsdescribed herein. If supercritical CO₂ is used as the non-solvent forthe active agent critical point drying can be used to form the coatinglayer.

In some embodiments of the present invention, non-solvent exchangecombined with one of the other methods described herein is used to fixthe coating layer morphology and active agent configuration. Forexample, after non-solvent exchange the configuration of the polymermatrix-active agent may be fixed by exposing the coating layer to liquidnitrogen. A desired phase separation of the active agents into theremaining coating layer solvent can be induced by partial non-solventexchange, for example with supercritical CO₂, after which exposing thecoating layer to liquid nitrogen or other morphology fixing methoddescribed herein can fix the selected configuration. Any remainingsolvent can be removed by one of the methods described herein. Forexample, this method can increase the release-rate of a portion of theactive agent by forming a desired amount of percolated phase within thecoating layer.

In yet another embodiment of the present invention, cross-linking thepolymer or polymers of the polymer matrix after coating the medicaldevice with the coating composition can fix the coating configuration,thereby locking the active agent into the desired phase structure,distribution, or morphology. Cross-linking can be accomplished by thechoice of polymers or prepolymers used to form the polymer matrix and,if necessary, the addition of a free radical or other cross-linkinginitiator or agent to the coating composition. The cross-linking agentor initiator can be added, for example in step (a) or (i) above, to thecoating composition, applied to the surface of the medical device andthe polymer matrix cross-linking activated before solvent removal.Solvent remaining in the coating layer after cross-linking maysubsequently be removed, for example, by evaporation, sublimation orother suitable method without inducing phase separation in the activeagent. After cross-linking the coating composition the coating layer maybe subjected to additional steps, for example, dipping in liquidnitrogen before removing the solvent by freeze-drying.

Examples of suitable methods for initiating cross-linking include, butare not limited to, heat (thermal initiators), light, ultraviolet (UV)radiation, infrared (IR) radiation, electron beam radiation or gammaradiation. In some embodiments, initiating cross-linking by a methodthat does not heat the coating composition aids in protecting heatsensitive active agents.

Cross-linking agents and initiators include, but are not limited to,photosensitizers for radiation curing of any monomers and macromonomers;catalysts for non-radiation curing of any monomers, macromonomers, orpolymers; and cross-linking agents such as zirconium compounds,aziridines, and isocyanates. Useful linking agents include, but are notlimited to, agents bearing hydroxyl, epoxide, carboxyl, amino, imide,aziridine, thiol, phosphoryl, aldehyde, anhydride, acyl halide, silyl,isocyanate, diisocyanate, carbodiimide, dihydrazide, multiaziridine,multifunctional carbodiimide, isothiocyanate or diamine functionalities.Further useful linking agents include, but are not limited to, polymersbearing a primary amine side group or groups, N-hydroxy-succinamide,acryloxy-terminated polyethylene glycol, and methacryloxy-terminatedpolyethylene glycol. Examples of cross-linking agents and initiatorsinclude, but are not limited to, formaldehyde, dialdehydes such asglutaraldeyde or succindialdehyde, di-epoxy reagents, diacrylates andmethacrylates such as polyethyleneglycol diacrylate, dia-azo compounds,di-N-hydroxy succinimide compounds, succinic anhydride, maleicanhydride, acetophenone, 2,2-dimethoxy-2-phenylacetophenone,1-hydroxycyclohexyl phenyl ketone, benzoin ethyl ether, benzophenone,camproquinone, and ethyl-4-N,N,-dimethyl aminobenzoate. Examples ofthermal initiators include, but are not limited to, those which formfree radicals at moderate temperatures, such as benzoyl peroxide with orwithout triethanolamine, potassium persulfate with or withouttetremethylethylenediamine, perammonium sulfate with sodium bisulfite,bis(2,4-dichlorobenzoyl)peroxide, dicumyl peroxide, 2,5-bis(tertbutylperoxy)-2,5-dimethyl hexane and 2,2′-azobisisobutyronitrile.

Another aspect of the present invention is to control the fraction ofsolvent removed from the wet coating layer before the desired activeagent morphology is fixed. By removing a known solvent fraction afterapplying the coating composition, the morphology of thepolymer-matrix-active-agent coating layer can be designed to have aselected amount of phase separation between the solvent and the polymermatrix and active agent phase, and thus a predetermined fraction of anactive agent phase. Hence, the active agent release-rate can be modifiedfor the most beneficial therapeutic effect in a subject.

In some embodiments, between about 1 and 90%, alternatively, betweenabout 1 and 80%, about 1 and 70%, about 1 and 60%, about 1 and 50%,about 1 and 25%, or about 1 and 10%, by weight of the solvent in thecoating composition is removed from the coating layer before thepolymer-matrix-active-agent configuration in the coating layer is fixed.

The percentage of an active agent phase present in a coating layer canbe selected by the methods described herein. The amount of a particularactive agent phase present in the coating layer can vary considerablyover the range from 0% to 100% based in the total amount of active agentin the coating layer. In one embodiment, the percentage of dissolvedphase is greater than the combined amount of dispersed and percolatedphase. In other embodiments, the percentage of dissolved phase is equalto or greater than the percentage of either dispersed or percolatedphase in the coating layer. In yet other embodiments, the percentage ofdissolved phase is less than the percentage of dispersed or percolatedphase in the coating layer. Designing the percentage of active agent indifferent phases can select the most therapeutically effectiverelease-rate. In some embodiment, the release-rate profile of activeagent from the coating layer is determined by the ratio of the phases ofthe active agent in the coating layer.

Coating layer thickness is from about 0.1 nm to about 1.0 cm, from about0.1 nm to about 1.0 mm, from about 0.1 nm to about 100 μm, from about0.1 nm to about 1 μm, from about 0.1 nm to about 100 nm, from about 0.1nm to about 10 nm, from about 10 nm to about 100 nm, from about 0.5 μmto about 10 μm, from about 1 μm to about 10 μm, from about 10 μm toabout 50 μm, from about 50 μm to about 100 μm, or any range therein. Inother embodiments, the thickness of the coating layer can be regionallydistributed throughout a device to create a variation in thicknessessuch as, for example, the variation in thicknesses present in anabluminally-coated drug-eluting stent (DES) systems.

Coating Compositions

The coating compositions of the present invention comprise one or moreactive agents, one or more polymers, and one or more solvents.Optionally, the coating composition may further comprise one or moreadditives or other components such as, for example, plasticizing agents,metals, metal oxides or ceramics.

Coating compositions are prepared by conventional methods, wherein allcomponents are combined and then blended. More particularly, adding apredetermined amount of polymer to a predetermined amount of acompatible solvent forms a polymer solution. The polymer can be added tothe solvent at ambient pressure, and under anhydrous or otheratmosphere. If necessary, gentle heating and stirring or mixing cancause the polymer to dissolve into the solvent, for example, 12 hours ina 60° C. water bath.

Sufficient amounts of active agent are dispersed in the blended polymersolution. The active agent preferably should be in true solution orsaturated in the blended composition. If the active agent is notcompletely soluble in the composition, operations including mixing,stirring, or agitation can be employed to homogenize the residuals.Alternatively, active agent can first be added to a compatible solventbefore mixing with the polymer solution. Optionally, a second solvent,such as tetrahydrofuran or dimethylformamide, can be used to improve thesolubility of an active agent in the coating composition or to increasethe composition's wetting ability. The second solvent can be added tothe coating composition or the active agent can be added to the secondsolvent before mixing with the polymer solution.

If additives and other components, for example cross-linking agents,plasticizers, or ceramics, are used these may be added and blended withthe coating composition at any step.

The amount of active agent in the coating layer should be the dosage orconcentration required to produce a therapeutic effect, and greater thanthe level at which non-therapeutic results are obtained. The dosage orconcentration of the active agent depends upon factors such as, forexample, the particular circumstances of the subject, the nature of thetrauma, the nature of the therapy desired, the time over which theingredient administered resides at the vascular site; and if otherbio-active substances are employed, the nature and type of the substanceor the combination of substances. The therapeutically effective dosagecan be determined by methods known in the art, such as for example,conducting suitable in vitro studies.

The one or more polymers of the polymer matrix can comprise from about0.1% to about 35%, and more narrowly from about 2% to about 20% byweight of the total weight of the coating composition. The one or moresolvents may comprise from about 19.8% to about 99.8%, more narrowlyfrom about 49% to about 87%, and yet more narrowly from about 79% toabout 87% by weight of the total weight of the coating compositions. Theone or more active agents may comprise from about 0.02% to about 40%,preferably from about 0.1% to about 9%, and more narrowly from about0.7% to about 1.2% by weight of the total weight of the coatingcomposition. Selection of a specific weight ratio of the polymer andsolvent depends on factors such as, but not limited to, the materialfrom which the device is made, the geometrical structure of the device,and the type and amount of active agent employed. The specific weightpercent of active agent depends on the polymer matrix-active agentmorphology of the coating layer and phases of active agent required, andfactors such as the dosage, duration of the release, cumulative amountof release, and the release-rate desired.

Solvents

The solvent should be capable of dissolving the polymer at theconcentration desired in the coating solution. Solvents useful forforming the coating compositions of the present invention are chosenbased on factors such as, for example, the solubility of the one or morepolymers in the solvent, compatibility with the active agents, thevolatility of the solvent, and the ability of the solvent to be removedfrom the coating layer after the coating layer configuration is fixed.Any suitable solvent, or mixture of solvents, that meets the criteriafor a coating solvent can be used.

Examples of suitable solvents for the practice of the present inventioninclude, but are not limited to, dimethylacetamide, dimethylformamide,tetrahydrofuran, cyclohexanone, acetone, acetonitrile, i-propanol,n-propanol, methanol, ethanol, butanol, propylene glycol monomethylether, methyl butyl ketone, methyl ethyl ketone, diethyl ketone, ethylacetate, n-butyl acetate, dioxane, chloroform, water (buffered saline),dimethylsulfoxide, dimethylformide, benzene, toluene, xylene, hexane,cyclohexane, pentane, heptane, octane, nonane, decane, decalin, i-butylacetate, i-propyl acetate, diacetone alcohol, benzyl alcohol,1-butanone, 2-butanone, N-methylpyrrolidinone, methylene chloride,carbon tetrachloride, tetrachloroethylene, tetachloroethane,chlorobenzene, 1,1,1-trichloroethane, formamide, hexafluoroisopropanol,1,1,1-trifluoroethanol, hexamethyl phosphoramide, and combinationthereof.

Application of Coating Composition onto a Medical Device.

Application of the coating composition onto the medical device can beaccomplished by any method known in the art. For example, the coatingcomposition may be applied to the medical device by casting, spraying,dipping or immersing, direct dispensing by hand or injection. Thecoating compositions of the present invention may be applied to all orto selected surfaces of a device. In alternative embodiments, where thecoating composition is used to form a medical device, the coatingcomposition can be injection molded or formed by other method known inthe art.

Operations such as wiping, centrifugation, blowing or other web-clearingacts may be performed to achieve a more uniform coating. Briefly, wipingrefers to physical removal of excess coating from the surface of thedevice; centrifugation refers to the rapid rotation of the device aboutan axis of rotation; and blowing refers to application of air at aselected pressure to the deposited coating. Excess coating may also bevacuumed off the surface of the device.

Before applying the coating layer to a medical device, the surface ofthe device should be clean and free from contaminants that may be havebeen introduced during manufacture. However, no particular surfacetreatment is required prior to applying the coating composition.Metallic surfaces of stents can, for example, be cleaned by an argonplasma process as is known to one of ordinary skill in the art.

A primer layer may optionally be used in the embodiments of the presentinvention to aid the adhesion of the coating layer to the devicesurface. This is particularly useful when the presence or concentrationof the active agent in the polymer matrix interferes with the ability ofthe polymer matrix to adhere effectively to the device surface. If anoptional primer layer is used, the primer layer is coated on the deviceor a portion of the device by any method described herein or known toone of ordinary skill in the art. The primer layer is dried (solventremoved) or cured before the coating composition comprising the polymermatrix and active agent is applied to the surface of the primer layer.Primer compositions may be prepared by adding a predetermined amount ofone or more polymers to a predetermined amount of solvent or mixture ofsolvents. Representative examples of polymers for the primer layerinclude, but are not limited to, polyisocyanates, polyethers,polyurethanes, acrylates, titanates, zirconates, silane coupling agents,high amine content polymers, polymers with a high content of hydrogenbonding groups, and unsaturated polymers and prepolymers. Representativeexamples of polymers also include those polymers used in the polymermatrices of the present invention as described herein. Further examplesof primer layers useful for the medical devices of the present inventioninclude those disclosed in U.S. Pat. No. 6,908,624 to Hossainy et al.,the disclosure of which is incorporated herein by reference.

Drying Coating Compositions

After coating the medical device and fixing the active agent morphology,solvent remaining in the wet coating layer is removed to form a drycoating layer. It is understood that by drying substantially all thesolvent, and wetting fluid if used, will be removed from the coatinglayer, but traces or residues can remain blended with the polymer. Inorder not to change the fixed morphology of the active agent in thecoating layer, the selected method should remove the solvent withoutcausing undesired phase separations or phase changes. Suitable methodsfor removing the solvent from the coating composition include, but arenot limited to, evaporation, freeze-drying (sublimation), non-solventexchange, critical point drying, or any combination thereof. Removal ofthe solvent may occur in a controlled atmosphere, for example humid,anhydrous or solvent saturated, at ambient pressure or under vacuum. Thetemperature at which the solvent is removed will depend on the method,and may vary over a wide range.

In one embodiment of the present invention, solvent in the wet coatinglayer is removed by freeze-drying. The method comprises first freezingthe coating layer, if the layer is not already in a frozen state, andthen placing the medical device under reduced pressure or in a vacuum sothat the solvent molecules vaporize (sublime) without the solventpassing through a liquid phase. The rate at which the coating layer isfrozen and solvent removed may vary over a wide range. In oneembodiment, the coating layer is frozen to 0° C. or less, alternativelyto −40° C. or less, −70° C. or less, −100° C. or less, and −150° C. orless.

In embodiments where the active agent morphology is fixed by shockfreezing or another method of reducing the temperature of the coatinglayer, solvent remaining in the coating layer can be removed, forexample, by freeze-drying the coating layer.

Evaporation of the solvent can occur at room temperature or be inducedby heating the device to a temperature for a period of time. Removal ofthe solvent may also occur in a controlled atmosphere, for examplehumid, anhydrous or solvent saturated, at ambient pressure or undervacuum. Conditions should be chosen so that they do not substantiallyadversely affect the active agent or the configuration of the activeagent. The coating layer can be heated at a temperature for a period oftime, for example, at 60° C. for 10 to 24 hours. The heating temperatureis chosen so as not to exceed temperatures at which the active agent isadversely affected.

In embodiments of the present invention where cross-linking is used tofix the active agent phase in the polymer matrix, a method such as, forexample, evaporation can remove residual solvent as described above.Solvent may also be removed by freeze-drying the coating layer aftercross-linking by freezing the coating layer and then freeze-drying.Other methods, as described herein, may also be used to remove anyremaining solvent from coating configurations fixed by cross-linking.

In yet another embodiment of the present invention, solvent of thecoating layer can be removed from the coating layer by exchange with anon-solvent for the active agent, and subsequent removal of thenon-solvent by one of the methods described herein. This can beaccomplished, for example, by exposing the wetpolymer-matrix-active-agent coating layer to the non-solvent. The chosennon-solvent should be miscible with the solvent of the coatingcomposition. In some invention embodiments, the non-solvent issubstantially miscible with the coating composition solvent. Examples ofsuitable non-solvents for the active agents include, but are not limitedto, supercritical CO₂, isopropyl alcohol, acetone, heptane and hexane,and blends thereof. Other examples of suitable solvents include, but arenot limited to, fluorocarbons and chlorofluorocarbons, for exampleFreon™ and HCFC 141b (dichlorofluoroethane), and blends of fluorocarbonsand alcohol such as, for example, dichlorofluoroethane blended withethanol. Non-solvent exchange may be carried out, for example, by methodsuch as liquid, spray or vapor mist contact. In those embodiments wheresupercritical CO₂ is used as the non-solvent for the active agent, thecoating layer may be dried by critical point drying. In some embodimentsthe coating layers of the present invention is dried by critical pointdrying.

Post-Formation Processing Steps

After drying the coating layers by removing solvent from the wetcoating, post-formation treatments optionally may be performed to thecoating layers and medical devices. Optional post-processing stepsinclude, but are not limited to, annealing the coating layer, applying aprotective coating, applying a rate-reducing membrane, diffusion barrierlayer or topcoat layer to the coating layer surface, applying anoptional finishing coat layer, and sterilization. The medical devicesmay further comprise an optional top-coat or barrier layer that, in someembodiments, controls the diffusion of the active agent out of thecoating layer. Outer coating layers can be applied over all or only aportion of the coating layer comprising the active agent. Examples oftopcoat layers and finishing coat layers are described, for example, inU.S. Patent Application Publication No. US 2005/0191332 to Hossainy, thedisclosure of which is incorporated herein by reference. Furtherexamples of outer layers, including rate-reducing membranes anddiffusion barrier layers, are described in U.S. Pat. No. 6,908,624 toHossainy et al., the disclosure of which is incorporated herein byreference. In some embodiments, the coating layer is annealed to removestresses. In these or other embodiments, annealing ameliorates coatinglayer brittleness caused by, for example, freeze-drying.

Medical Devices

Throughout this application “medical device” or “medical article” areused interchangeably, and refer to any device or article that can beused in the medical treatment of a human or veterinary subject. Medicaldevices may be used either externally on a subject or implanted in asubject. In a preferred embodiment, the medical device is implantable.An example of an implantable medical device is a stent, which can beimplanted into a human or veterinary patient. While examples of coatinga device such as a drug eluting or delivery stent are described herein,one of skill in the art will appreciate that other medical devices andsubstrates can be manufactured using the methods of the presentinvention. Examples of medical devices include, but are not limited to,stents, stent-grafts, vascular grafts, artificial heart valves, foramenovale closure devices, cerebrospinal fluid shunts, pacemaker electrodes,guidewires, ventricular assist devices, cardiopulmonary bypass circuits,blood oxygenators, coronary shunts vena cava filters, and endocardialleads. Examples of stents include, but are not limited to, tubularstents, self-expanding stents, coil stents, ring stents, multi-designstents, and the like. In some embodiments, the stents include, but arenot limited to, vascular stents, renal stents, biliary stents, pulmonarystents and gastrointestinal stents.

The underlying structure of the medical device can be virtually anydesign. The medical device can be comprised of a metallic material oralloy, low-ferromagnetic, non-ferromagnetic, biostable polymeric,biodegradable polymeric, bioabsorbable polymers, biodegradable metallicor other compatible material known in the art. In yet furtherembodiments, the medical devices may be formed from the coatingcompositions comprising one or more polymers and one or more activeagents by, for example, injection molding and other methods as known toone skilled in the art. Examples of metals and alloys include, but arenot limited to, ELASTINITE®, NITINOL® (Nitinol Devices and Components,Fremont, Calif.), stainless steel, tantalum, tantalum-based alloys,nickel-titanium alloys, platinum, platinum-based alloys such as, forexample, platinum-iridium alloys, iridium, gold, magnesium, titanium,titanium-based alloys, zirconium-based alloys, alloys comprising cobaltand chromium (ELGILOY®, Elgiloy Specialty Metals, Inc., Elgin, Ill.;MP35N and MP20N, SPS Technologies, Jenkintown, Pa.) or combinationsthereof. The trade names “MP35N” and “MP20N” describe alloys of cobalt,nickel, chromium and molybdenum. The MP35N consists of 35% cobalt, 35%nickel, 20% chromium, and 10% molybdenum. The MP20N consists of 50%cobalt, 20% nickel, 20% chromium, and 10% molybdenum.

Active Agents

The coating compositions of the present invention comprise one or moreactive agents. If combinations of active agents are used, each agent ischosen with regard to its compatibility with other agents and polymersof the matrix, and with regard to its release-rate from the polymermatrix. The term “active agent” refers to any substance that is capableof providing a therapeutic, prophylactic or other biological effectwithin a subject. An active agent can also be a diagnostic agent, or befor enhancing wound healing in a vascular site or improving thestructure and elastic properties of a vascular site. An active agent canbe a drug. Examples of suitable active agents include syntheticinorganic and organic compounds, proteins and peptides, polysaccharidesand other sugars, lipids, and DNA and RNA nucleic acid sequences havingtherapeutic, prophylactic or diagnostic activities.

Active agents of the coating compositions can form linkages with thepolymer matrix when blended or mixed into the coating composition orformed into coatings of the present invention. If linkages form theconnections may be physical, chemical, or a combination thereof.Examples of physical connections include, but are not limited to, aninterlinking of components that can occur, for example, ininterpenetrating networks and chain entanglement. Examples of chemicalconnections include, but are not limited to, covalent and non-covalentbonds. Non-covalent bonds include, but are not limited to, ionic bondsand inter-molecular attractions such as, for example, hydrogen bonds andelectrostatic interactions or attractions. The polymers can also beblended or mixed with the active agents. In some embodiments, the activeagents do not form covalent bonds with the polymer matrix. If more thanone agent is present in the coating, each agent may form a differenttype of linkage or no linkage.

A wide range of different active agents can be incorporated into themedical devices' of the present invention. These include hydrophobic,hydrophilic, and high molecular weight macromolecules such as proteins.The active agent can be incorporated into a polymeric matrix in apercent loading of between 0.01% and 70%, alternatively, between 5% and50% by weight.

Examples of active agents include, but are not limited to,antiproliferative, antineoplastic, anti-inflammatory, steroidalanti-inflammatory, non-steroidal anti-inflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,antiallergic, antioxidant, and cytostatic agents, and combinationsthereof.

Examples of antiproliferative substances include, but are not limited,to actinomycin D, or derivatives and analogs thereof (manufactured bySigma-Aldrich of Milwaukee, Wis., or COSMEGEN available from Merck,Whitehouse Station, N.J.). Synonyms of actinomycin D includedactinomycin, actinomycin IV, actinomycin I₁, actinomycin X₁, andactinomycin C₁. Examples of antineoplastics and/or antimitotics include,but are not limited to, paclitaxel (e.g. TAXOL® by Bristol-Myers SquibbCo., Stamford, Conn.), docetaxel (e.g. TAXOTERE®., from Aventis S. A.,Frankfurt, Germany), methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. ADRIAMYCIN®from Pharmacia & Upjohn, Peapack, N.J.), and mitomycin (e.g. MUTAMYCIN®from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofantiplatelets, anticoagulants, antifibrins, and antithrombins include,but are not limited to, heparin, sodium heparin, low molecular weightheparins, heparin sulfate, heparinoids, hirudin, argatroban, forskolin,vapiprost, prostacyclin and prostacyclin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody,recombinant hirudin, thrombin inhibitors such as ANGIOMAX™ (Biogen,Inc., Cambridge, Mass.), and 7E-3B® (an antiplatelet drug from Centocor,Horsham, Pa.). Examples of suitable antimitotic agents include, but arenot limited to, methptrexate, azathioprine, vincristine, vinblastine,fluorouracil, adriamycin, and mutamycin. Examples of such cytostatic orantiproliferative agents include, but are not limited to, angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.CAPOTEN® and CAPOZIDE® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. PRINIVIL® and PRINZIDE® from Merck & Co.,Inc., Whitehouse Station, N.J.), calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagorists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMEVACOR® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include, but are not limited to, alpha-interferon,genetically engineered epithelial cells, tacrolimus, dexamethasone, andrapamycin and structural derivatives or functional analogs thereof, suchas 40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name ofEverolimus available from Novartis Pharma AG, Switzerland),40-O-(3-hydroxy)propyl-rapamycin,40-O—[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.

Example of diagnostic agents include, but are not limited to, thosedetectable by x-ray, fluorescence, magnetic resonance imaging,radioactivity, ultrasound, computer tomography (CT), and positronemission tomography (PET).

The foregoing substances are listed by way of example and are not meantto be limiting. Other active agents that are currently available or thatmay be developed in the future are equally applicable.

Polymer Matrices

The coating layers of the present invention comprise a polymer matrix,composed of one or more polymers. The one or more polymers comprisingthe polymer matrix may be in mixed, blended or conjugated form. Thepolymer matrices and coating compositions of the present invention mayalso be used to form medical devices by a process such as, for example,molding.

There is a wide choice of polymer and copolymers for use in the polymermatrix of the present invention. The chosen polymer matrix must be onethat is biocompatible and minimizes irritation when implanted. Thechoice of the matrix components depends on numerous factors including,but not limited to, the interactions between the polymer(s) and theagent(s) and/or solvent(s), the biocompatibility of the polymer(s), andthe physical, mechanical, chemical and biological properties of thepolymers. Performance parameters include, for example, the ability toadhere to the surface of the medical device, the toughness of thecoating desired, the capacity for the loading concentration of an agent,and the rate of biodegradation and elimination of the composition from asubject.

Each of the one or more polymers chosen for the matrix can be eitherbiostable or biodegradable. “Biodegradable” refers to polymers that arecapable of being completely degraded and/or eroded when exposed tobodily fluids such as blood and can be gradually resorbed, absorbedand/or eliminated from the subject. The process of breaking down andeventual absorption and elimination of the polymer can be caused by, forexample, hydrolysis, metabolic processes, bulk or surface erosion, andthe like. After biodegradation traces or residual polymer may remain onthe device or near the device. Examples of biodegradable polymersinclude, but are not limited to, polymers having repeating units suchas, for example, an α-hydroxycarboxylic acid, a cyclic diester of anα-hydroxycarboxylic acid, a dioxanone, a lactone, a cyclic carbonate, acyclic oxalate, an epoxide, a glycol, an anhydride, a lactic acid, aglycolic acid, a lactide, a glycolide, an ethylene oxide, an ethyleneglycol, or combinations thereof. In some embodiments, the polymer matrixreleases active agent during biodegradation. In other embodiments, thepolymer matrix releases active agent without biodegradation of thematrix. In yet other embodiments, the release of active agent may bepartially dependent on biodegradation of the polymer matrix. Biostablepolymers should have a relatively low chronic tissue response.

The polymers useful for the polymer matrixes of the present inventioninclude, but are not limited to, natural or synthetic polymers,condensation polymers, homopolymers and copolymers or any combinationand/or blend thereof. Polymers may be hydrophobic, hydrophilic, or acombination thereof. Copolymers may be random, alternating, block,graft, and/or crosslinked, and may include polymers with more than twodifferent types of repeating units such as terpolymers. In someembodiments, the polymers are selected such that they specificallyexclude any one or any combination of any of the polymers taught herein.

Representative examples of polymers that can be used in the polymermatrices and coating compositions of the present invention include, butare not limited to, poly(acrylates) (such as poly(methacrylates),polymethyl methacrylate and polybutyl methacrylate), acrylic polymersand copolymer (such as polyacrylonitrile), poly(cyanoacrylates),fluorinated polymers or copolymers (such as polyfluoro-alkylenes,polyvinylidene fluoride-co-hexafluoropropene andpolytetrafluoroethylene), polycaprolactones, polylactides,poly(D-lactides), poly(L-lactides), poly(D,L-lactides), Poly(lacticacids), poly(glycolic acid), poly(lactide-co-glycolide), poly(glycolicacid-co-trimethylene carbonate), poly(lactic acid-co-trimethylenecarbonate, poly(amino acids), polyhydroxyalkanoates,poly(hydroxyvalerate), polyhydroxybutyrates,poly(hydroxybutyrate-co-valerate), polymers and copolymers ofhydroxylethyl methacryate, polydioxanones, polyorthoesters,polyanhydrides, polyphosphoesters, polyphosphoester urethanes,polyphosphazenes, polycarbonates, polyiminocarbonates, polytrimethylenecarbonates, co-poly(ether-esters) (such as polyethylene oxide/polylacticacid (PEO/PLA)), poly(alkylene oxalates), polyurethanes, silicones,polyesters, polyolefins (such as polyethylene and polypropylene),poly(isobutylene) and ethylene-alphaolefin copolymers, vinyl halidepolymers and copolymers (such as polyvinyl chloride), polyvinyl ethers(such as polyvinyl methyl ether), polyvinylidene halides (such aspolyvinylidene fluoride and polyvinylidene chloride), polyacrylonitrile,polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinylesters (such as polyvinyl acetate), copolymers of vinyl monomers witheach other and olefins (such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers), ethylene vinyl alcohol copolymers (such as ethylene vinylalcohol co-polymer, commonly know by the generic name EVOH or by thetrade name EVAL), polyamides (such as Nylon 66 and polycaprolactam),alkyd resins, polyoxymethylenes, polyimides, polyester amides,polyethers including poly(alkylene glycols) (such as poly(ethyleneglycol) and poly(propylene glycol)), poly(tyrosine derived carbonates),poly(tyrosine derived arylates), epoxy resins, rayon, rayon-triacetate,biomolecules (such as fibrin, fibrinogen, starch, cellulose, collagen,hyaluronic acid), poly(N-acetylglucosamine) (chitin), chitosan,cellulose, cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, CELLOPHANE, cellulose nitrate, cellulose propionate, celluloseethers, and carboxymethyl-cellulose, and derivatives, copolymers andcombinations of the foregoing. In some embodiments, the polymer canexclude any one or any combination of the aforementioned polymers.

Plasticizing Agents

The coating compositions and coating layers of the present invention mayfurther comprise one or more plasticizing agents. The terms“plasticizer” and “plasticizing agent” can be used interchangeably inthe present invention, and refer to any agent, including any agentdescribed above, where the agent can be added to a polymeric compositionto modify the mechanical properties of the composition or a productformed from the composition. Plasticizers can be added, for example, toreduce crystallinity, lower the glass-transition temperature (T_(g)), orreduce the intermolecular forces between polymers. The mechanicalproperties that are modified include, but are not limited to, Young'smodulus, impact resistance (toughness), tensile strength, and tearstrength. Impact resistance, or “toughness,” is a measure of energyabsorbed during fracture of a polymer sample of standard dimensions andgeometry when subjected to very rapid impact loading. Toughness can bemeasured using Charpy and Izod impact tests to assess the brittleness ofa material.

A plasticizer can be monomeric, polymeric, co-polymeric, or acombination thereof, and can be combined with a polymeric composition inthe same manner as described above. Plasticization and solubility areanalogous in the sense that selecting a plasticizer involvesconsiderations similar to selecting a solvent such as, for example,polarity. Furthermore, plasticization can also be provided throughcovalent bonding by changing the molecular structure of the polymerthrough copolymerization.

Examples of plasticizing agents include, but are not limited to, lowmolecular weight polymers (such as single-block polymers, multi-blockcopolymers, and other copolymers such as graft copolymers), oligomers(such as ethyl-terminated oligomers of lactic acid), small organicmolecules, hydrogen bond forming organic compounds with and withouthydroxyl groups, polyols (such as low molecular weight polyols havingaliphatic hydroxyls), alkanols (such as butanols, pentanols andhexanols), sugar alcohols and anhydrides of sugar alcohols, polyethers(such as poly(alkylene glycols)), esters (such as citrates, phthalates,sebacates and adipates), polyesters, aliphatic acids, proteins (such asanimal proteins and vegetable proteins), oils (such as, for example, thevegetable oils and animal oils), silicones, acetylated monoglycerides,amides, acetamides, sulfoxides, sulfones, pyrrolidones oxa acids,diglycolic acids, and any analogs, derivatives, copolymers andcombinations of the foregoing.

The amount of plasticizer used in the present invention, can range fromabout 0.001% to about 70%; from about 0.1% to about 50%; from about 0.6%to about 30%; from about 0.75% to about 25%; from about 1.0% to about10%; and any range therein, as a weight percentage based on the totalweight of the polymer and agent or combination of agents.

It should be appreciated that any one or any combination of theplasticizers described above can be used in the present invention. Forexample, the plasticizers can be combined to obtain the desiredfunction. In some embodiments, a secondary plasticizer is combined witha primary plasticizer in an amount that ranges from about 0.001% toabout 20%; from about 0.05% to about 10%; from about 1.0% to about 5%,or any range therein, as a weight percentage based on the total weightof the polymer, any agent or combination of agents in the coating layer.

Plasticizers may also be combined with other agents to obtain otherdesired functions such as, for example, an added therapeutic,prophylactic, and/or diagnostic function. In some embodiments, theplasticizers can be linked to other agents through ether, amide, ester,orthoester, anhydride, ketal, acetal, carbonate, and all-aromaticcarbonate linkages.

Other Additives and Components of the Coating Compositions

The coating compositions and coating layers of the present invention mayoptionally further comprise one or more other additives or components.For example, the polymer matrix may be combined with ceramics and/ormetals. Examples of ceramics include, but are not limited to,hydroxyapatite, BIOGLASS®, and absorbable glass. Examples of metalsinclude, but are not limited to magnesium, copper, titanium, andtantalum.

While particular embodiments of the present invention have beendescribed, it will be obvious to those skilled in the art that changesand modifications can be made without departing from the spirit andscope of the teachings and embodiments of this invention. One skilled inthe art will appreciate that such teachings are provided in the way ofexample only, and are not intended to limit the scope of the invention.Therefore, the appended claims are to encompass within their scope allsuch changes and modifications as fall within the true spirit of thisinvention.

1. A method comprising: preparing a coating composition comprising one or more polymers, one or more active agents, and one or more solvents; applying the coating composition onto a medical device to form a wet coating layer; fixing a morphology of the one or more active agents; and removing solvent from the wet coating layer to form a coating layer.
 2. The method of claim 1 wherein the morphology is fixed by a method selected from the group consisting of exposing to cold gas, dipping in cold liquid, exposing to shock freezing, exposing to flash vaporization, exposing to a non-solvent exchange, and combinations thereof.
 3. The method of claim 1 wherein the morphology is fixed by cross-linking the polymer matrix.
 4. The method of claim 1 further comprising removing a fraction of the solvent from the wet coating layer before fixing the morphology.
 5. The method of claim 4 wherein the fraction is between about 1 and 90% by weight of solvent.
 6. The method of claim 4 wherein the fraction is between about 1 and 50% by weight of solvent.
 7. The method of claim 1 wherein the solvent is removed by a method selected from the group consisting of evaporation, freeze-drying, non-solvent exchange, critical point drying, and combinations thereof.
 8. The method of claim 4 wherein the fraction of the solvent is removed by a method selected from the group consisting of evaporation, freeze-drying, non-solvent exchange, critical point drying, and combinations thereof.
 9. The method of claim 7 wherein the non-solvent is selected from the group consisting of supercritical CO₂, isopropyl alcohol, acetone, heptane, hexane, ethanol, fluorocarbons, chlorofluorocarbons, and blends thereof.
 10. The method of claim 7 wherein the non-solvent is supercritical CO₂.
 11. The method of claim 10 wherein solvent is removed by critical point drying.
 12. The method of claim 1 wherein after forming the coating layer the method comprises one or more post-formation process steps.
 13. The method of claim 12 wherein the post-formation process steps are selected from the group consisting of annealing, applying a topcoat coating or barrier layer to the surface of the coating layer, applying a finishing coat layer, and sterilizing.
 14. The method of claim 1 wherein the volume fraction of active agent to polymer in the coating layer is about 35% or greater.
 15. The method of claim 1 wherein the volume fraction of active agent to polymer in the coating layer is about 25% or greater.
 16. The method of claim 1 wherein the volume fraction of active agent to polymer in the coating layer is about 10% or greater.
 17. The method of claim 1 wherein the active agent comprises from about 0.02 to about 40% by weight of the total weight of the coating composition.
 18. The method of claim 1 wherein the active agent comprises from about 0.1 to about 9% by weight of the total weight of the coating composition.
 19. The method of claim 1 wherein the polymer comprises from about 0.1 to about 35% by weight of the total weight of the coating composition.
 20. The method of claim 1 wherein the solvent comprises from about 19.8 to about 99.8% by weight of the total weight of the coating composition.
 21. The method of claim 1 wherein the active agent morphology is fixed in a phase distribution comprising one or more of dissolved phase, dispersed phase and percolated phase.
 22. The method of claim 21 wherein the phase distribution comprises primarily dissolved phase.
 23. The method of claim 21 wherein the phase distribution comprises primarily dispersed phase.
 24. The method of claim 21 wherein the phase distribution comprises primarily dissolved phase and dispersed phase.
 25. The method of claim 21 wherein the phase distribution of active agent comprises dissolved phase, dispersed phase and percolated phase, and wherein the amount of dissolved phase in the coating layer is greater than the amount of either dispersed or percolated phase.
 26. The method of claim 21 wherein the release-profile of active agent from the coating layer is determined by the phase distribution of the one or more active agent phases in the coating layer.
 27. The method of claim 1 wherein the volume fraction of active agent in the coating layer is at the percolation threshold, and where the active agent morphology is fixed primarily in a phase distribution other than the percolated phase.
 28. The method of claim 1 wherein the coating composition further comprises a cross-linking agent or initiator.
 29. The method of claim 1 wherein the coating layer further comprises one or more additives selected from the group consisting of plasticizers, metals, and ceramics.
 30. The method of claim 1 wherein the medical device comprises a primer layer, and the coating composition is coated on all or part of the primer layer.
 31. The method of claim 1 wherein the medical device is a stent.
 32. The method of claim 1 wherein the one or more active agents are selected from the group consisting of antiproliferative, antineoplastic, anti-inflammatory, steroidal anti-inflammatory, non-steroidal anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic, antioxidant, cytostatic agents, and combinations thereof.
 33. The method of claim 1 wherein the one or more polymers are selected from the group consisting of poly(acrylates), acrylic polymers and copolymer, poly(cyanoacrylates), fluorinated polymers or copolymers, polycaprolactones, polylactides, poly(D-lactides), poly(L-lactides), poly(D,L-lactides), Poly(lactic acids), poly(glycolic acid), poly(lactide-co-glycolide), poly(glycolic acid-co-trimethylene carbonate), poly(lactic acid-co-trimethylene carbonate, poly(amino acids), polyhydroxyalkanoates, poly(hydroxyvalerate), polyhydroxybutyrates, poly(hydroxybutyrate-co-valerate), polymers and copolymers of hydroxylethyl methacryate, polydioxanones, polyorthoesters, polyanhydrides, polyphosphoesters, polyphosphoester urethanes, polyphosphazenes, polycarbonates, polyiminocarbonates, polytrimethylene carbonates, co-poly(ether-esters), poly(alkylene oxalates), polyurethanes, silicones, polyesters, polyolefins, poly(isobutylene) and ethylene-alphaolefin copolymers, vinyl halide polymers and copolymers, polyvinyl ethers, polyvinylidene halides, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, polyvinyl esters (such as polyvinyl acetate), copolymers of vinyl monomers with each other and olefins, ethylene vinyl alcohol copolymers, polyamides, alkyd resins, polyoxymethylenes, polyimides, polyester amides, polyethers including poly(alkylene glycols), poly(tyrosine derived carbonates), poly(tyrosine derived arylates), epoxy resins, rayon, rayon-triacetate, biomolecules, poly(N-acetylglucosamine), chitosan, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, CELLOPHANE, cellulose nitrate, cellulose propionate, cellulose ethers, and carboxymethyl-cellulose, and derivatives, copolymers and combinations thereof.
 34. The method of claim 1 wherein the one or more solvents are selected from the group consisting of dimethylacetamide, dimethylformamide, tetrahydrofuran, cyclohexanone, acetone, acetonitrile, i-propanol, n-propanol, methanol, ethanol, butanol, propylene glycol monomethyl ether, methyl butyl ketone, methyl ethyl ketone, diethyl ketone, ethyl acetate, n-butyl acetate, dioxane, chloroform, water (buffered saline), dimethylsulfoxide, dimethylformide, benzene, toluene, xylene, hexane, cyclohexane, pentane, heptane, octane, nonane, decane, decalin, i-butyl acetate, i-propyl acetate, diacetone alcohol, benzyl alcohol, 1-butanone, 2-butanone, N-methylpyrrolidinone, methylene chloride, carbon tetrachloride, tetrachloroethylene, tetachloroethane, chlorobenzene, 1,1,1-trichloroethane, formamide, hexafluoroisopropanol, 1,1,1-trifluoroethanol, hexamethyl phosphoramide, and mixtures thereof.
 35. A coating layer for a medical device comprising a polymer matrix and an active agent, wherein the active agent phase distribution comprises one or more of the group consisting of dissolved phase, dispersed phase and percolated phase; and the release-rate profile of active agent is determined by the ratio of the one or more phases of the active agent in the coating layer.
 36. The coating of claim 35 wherein the volume fraction of active agent to polymer matrix in the coating layer is about 35% or greater.
 37. The coating of claim 35 wherein the volume fraction of active agent to polymer in the coating layer is about 25% or greater.
 38. The coating of claim 35 wherein the volume fraction of active agent to polymer in the coating layer is about 10% or greater.
 39. The coating of claim 35 wherein the phase distribution comprises primarily dissolved phase.
 40. The coating of claim 35 wherein the phase distribution comprises primarily dispersed phase.
 41. The method of claim 35 wherein the phase distribution comprise primarily dissolved phase and dispersed phase.
 42. The coating of claim 35 wherein the volume fraction of active agent in the coating layer is at the percolation threshold, and where the active agent phase distribution comprises primarily a phase other than the percolated phase. 